Sequence inversion and phenylalanine surrogates at the beta-turn enhance the antibiotic activity of gramicidin S
| Autor: | Clara M. Santiveri, María José Fernández-Reyes, Concepción Solanas, Luis Rivas, Beatriz G. de la Torre, David Andreu, Carlos Cativiela, Ana I. Jiménez, M. Angeles Jiménez |
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| Předmět: |
Magnetic Resonance Spectroscopy
Stereochemistry medicine.drug_class Phenylalanine Antibiotics β-sheet structure Gramicidin S Microbial Sensitivity Tests Gram-Positive Bacteria Gramidicin S Hemolysis Article Protein Structure Secondary chemistry.chemical_compound Structure-Activity Relationship β-turn Drug Discovery Drug Resistance Bacterial Gram-Negative Bacteria Cationic antimicrobial peptides medicine Structure–activity relationship Animals Sequence Inversion Sheep Chemistry Hydrogen bond Gramicidin Hydrogen Bonding Nuclear magnetic resonance spectroscopy NMR Anti-Bacterial Agents Biochemistry Phenylalanine analogs Molecular Medicine |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname Digital.CSIC. Repositorio Institucional del CSIC |
| Popis: | A series of gramicidin S (GS) analogues have been synthesized where the Phe (i + 1) and Pro (i + 2) residues of the β-turn have been swapped while the respective chiralities (d-, l-) at each position are preserved, and Phe is replaced by surrogates with aromatic side chains of diverse size, orientation, and flexibility. Although most analogues preserve the β-sheet structure, as assessed by NMR, their antibiotic activities turn out to be highly dependent on the bulkiness and spatial arrangement of the aromatic side chain. Significant increases in microbicidal potency against both Gram-positive and Gram-negative pathogens are observed for several analogues, resulting in improved therapeutic profiles. Data indicate that seemingly minor replacements at the GS β-turn can have significant impact on antibiotic activity, highlighting this region as a hot spot for modulating GS plasticity and activity. © 2010 American Chemical Society. This work was supported by Ministerio de Ciencia e Innovación (BIO2008-04487-CO3-02 to D.A., CTQ2008-00080/BQU to M.A.J., CTQ2007-62245 to C.C.), Fondo de Investigaciones Sanitarias (PI061125, PS09/1928, and RD06/0021/0006 to L.R.), by the regional governments of Aragón (research group E40), Catalonia (SGR2008-492), and Madrid (COMBACT S-BIO-0260/2006). C.S. and C.M.S. thank Ministerio de Educación y Ciencia and Consejo Superior de Investigaciones Científicas-European Social Fund for FPU and I3P fellowships, respectively. |
| Databáze: | OpenAIRE |
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